The goal of this project has been to examine the central nervous system effects of changes in reproductive endocrine function occurring in the context of hypogonadism. Investigations have been primarily focused on the characterization of affective disorders occurring during the perimenopause and midlife, the identification of the role of gonadal steroids in these mood disorders, and the examination of the neuroregulatory consequences of the presence and absence of gonadal steroids in women and men. Finally, the information obtained by these protocols will help identify the predictive utility of endocrine measures in perimenopausal depression and help define the role of hormonal therapies in mood disorders occurring at midlife in men and women. Findings to date: 1) a significant improvement in measures of depression and libido after DHEA administration was seen in 46 men and women with midlife-related major and minor depression; 2) neither gender nor plasma hormone levels predicted the therapeutic response to DHEA administration in midlife-related depression; 3) neither short term (six week) nor long term (six months-one year) administration of DHEA significantly altered measures of bone metabolism or bone density; 4) a significant improvement in measures of depression was seen after six weeks of either estradiol or the SERM raloxifene, but not after either placebo or phytoestrogen in 25 women with perimenopausal depression who have completed a double-blind, placebo-controlled, parallel design trial; 5) raloxifene also was associated with an increase in plasma estradiol levels; 6) women with a past perimenopausal depression but not those without such a history experience mood symptoms during short term estradiol withdrawal under blinded, placebo-controlled conditions; and 7) we observed a higher than expected co-occurrence of prospectively confirmed premenstrual dysphoria and perimenopausal depression. In a study involving the induction of hypogonadism in men and women with GnRH agonists, we have observed the hypogonadal state to be associated with the following: 1) the development of clinically significant mood symptoms in approximately 10% of hypogonadal men and women despite the presence of hot flushes and loss of libido in 90-100% of these men; 2) the prediction of greater declines in sexual functioning during hypogonadism in both men and women by baseline (higher) sexual function but not hormone levels; 3)the correlation between CSF measures of the neurosteroid androsterone but not testosterone and sexual function in men during both hypogonadism and testosterone replacement; and 4) the elimination in women of both cognition activated regional cerebral blood flow (O15 3D PET scans) in the dorsolateral prefrontal cortex and the reciprocal functional connectivity between the left hippocampal formation and the contralateral dorsolateral prefrontal cortex compared to either estradiol or progesterone replacement. In collaboration with NICHD we have observed that women with Turner Syndrome (n = 100) have significantly higher scores on measures of shyness, depression and anxiety than asymptomatic controls (n = 35) but their scores do not differ from those in women with premature ovarian failure (POF) (n =100). Finally, women with POF report an increased frequency of past episodes of depression compared to community samples of women, and the majority of these depressive episodes occurred in the context of menstrual cycle irregularity preceding their final menstrual period and the diagnosis of POF.